Pregnancy-related Factors Responsible for Delivering Low Birth Weight Babies: An Institutional-based Cross-sectional Study, Jamnagar, Gujarat.

Background: The WHO defines LBW as "Birth weight less than 2500 grams" regardless of gestational age. Being born with a low birth weight also incurs enormous economic costs, including higher medical expenditures and social service expenses, and decreased productivity in adulthood. Objective: To study distribution of newborns' according to pregnancy related factors and its association with newborns' birth weight. Methods: An institutional based cross-sectional study. New-borns delivered at study institute were considered as study participants. Estimated final sample size was 500. Guardians (mothers) were face-to-face interviewed and also recorded data were collected from the case file and Mother and Child Protection Card. Results: Prevalence of LBW newborns was higher in mothers with late ANC registration, <4 ANC visits, chronic medical conditions, infection during pregnancy, PIH, anemia, consuming tobacco, exposure to second hand smoke, LSCS/Assisted delivery, in female newborns', current pregnancy birth order number more than 2, in pre term newborns' and mothers with bad obstetric history. Conclusion: Create awareness and adoption of suitable family planning methods. Need to do early (within 12 weeks) ANC registration with minimum four ANC visits for better pregnancy outcome. Effective tracking and suitable intervention provided to improve current pregnancy outcome. Health care professional should pay special attention to high-risk pregnancy. Develop social culture in such a way that females are neither addicted nor exposed to any tobacco containing products in their life.

Discovery and pharmacological evaluation of indole derivatives as potent and selective RORγt inverse agonist for multiple autoimmune conditions.

Targeting nuclear receptor RORγ is recognized to be beneficial in multiple autoimmune disorders. We disclosed new indole analogues as potent RORγ inverse agonists. RO-2 as one of the potent and orally bioavailable compounds was evaluated in various models of autoimmune disorder. It showed potent suppression of downstream markers of RORγt activity in murine and human primary cells, ex vivo PD assay and in multiple animal models of autoimmune diseases. The results indicate the potential of these indole analogues as orally bioavailable small molecule inverse agonists of RORγt, efficacious in various Th17 driven models of autoimmune disorders.

Antitumor Efficacy of the Dual PI3K/mTOR Inhibitor PF-04691502 in a Human Xenograft Tumor Model Derived from Colorectal Cancer Stem Cells Harboring a PIK3CA Mutation.

PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) mutations can help predict the antitumor activity of phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway inhibitors in both preclinical and clinical settings. In light of the recent discovery of tumor-initiating cancer stem cells (CSCs) in various tumor types, we developed an in vitro CSC model from xenograft tumors established in mice from a colorectal cancer patient tumor in which the CD133+/EpCAM+ population represented tumor-initiating cells. CD133+/EpCAM+ CSCs were enriched under stem cell culture conditions and formed 3-dimensional tumor spheroids. Tumor spheroid cells exhibited CSC properties, including the capability for differentiation and self-renewal, higher tumorigenic potential and chemo-resistance. Genetic analysis using an OncoCarta™ panel revealed a PIK3CA (H1047R) mutation in these cells. Using a dual PI3K/mTOR inhibitor, PF-04691502, we then showed that blockage of the PI3K/mTOR pathway inhibited the in vitro proliferation of CSCs and in vivo xenograft tumor growth with manageable toxicity. Tumor growth inhibition in mice was accompanied by a significant reduction of phosphorylated Akt (pAKT) (S473), a well-established surrogate biomarker of PI3K/mTOR signaling pathway inhibition. Collectively, our data suggest that PF-04691502 exhibits potent anticancer activity in colorectal cancer by targeting both PIK3CA (H1047R) mutant CSCs and their derivatives. These results may assist in the clinical development of PF-04691502 for the treatment of a subpopulation of colorectal cancer patients with poor outcomes.

Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line.

Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell (CSC) populations. In this study, we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell line. Treating these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell populations. However, the CSC-like cells exhibited resistance to gemcitabine-induced apoptosis. Collectively, the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs.

Biochemical and pharmacological characterization of human c-Met neutralizing monoclonal antibody CE-355621.

The c-Met proto-oncogene is a multifunctional receptor tyrosine kinase that is stimulated by its ligand, hepatocyte growth factor (HGF), to induce cell growth, motility and morphogenesis. Dysregulation of c-Met function, through mutational activation or overexpression, has been observed in many types of cancer and is thought to contribute to tumor growth and metastasis by affecting mitogenesis, invasion, and angiogenesis. We identified human monoclonal antibodies that bind to the extracellular domain of c-Met and inhibit tumor growth by interfering with ligand-dependent c-Met activation. We identified antibodies representing four independent epitope classes that inhibited both ligand binding and ligand-dependent activation of c-Met in A549 cells. In cells, the antibodies antagonized c-Met function by blocking receptor activation and by subsequently inducing downregulation of the receptor, translating to phenotypic effects in soft agar growth and tubular morphogenesis assays. Further characterization of the antibodies in vivo revealed significant inhibition of c-Met activity (≥ 80% lasting for 72-96 h) in excised tumors corresponded to tumor growth inhibition in multiple xenograft tumor models. Several of the antibodies identified inhibited the growth of tumors engineered to overexpress human HGF and human c-Met (S114 NIH 3T3) when grown subcutaneously in athymic mice. Furthermore, lead candidate antibody CE-355621 inhibited the growth of U87MG human glioblastoma and GTL-16 gastric xenografts by up to 98%. The findings support published pre-clinical and clinical data indicating that targeting c-Met with human monoclonal antibodies is a promising therapeutic approach for the treatment of cancer.

Internal fixation of fractures of both bones forearm: Comparison of locked compression and limited contact dynamic compression plate.

BACKGROUND: The locking compression plate (LCP) with combination holes is a newer device in fracture fixation. We undertook a study comparing the LCP with limited contact dynamic compression plate (LC-DCP) in the treatment of diaphyseal fractures of both bones of the forearm. MATERIALS AND METHODS: This is a prospective comparative study, 36 patients (18 in each group) with fractures of both the forearm bones (72 fractures) were treated with one of the two devices. The average age of the patients was 30.5 years (range 16-60 years) with mean followup of 2.1 years (range 1.5-2.8 years). The patients were assessed for fracture union and function and complications and by Disabilities of the Arm, Shoulder and Hand (DASH) score for patient related outcome at the latest followup. RESULTS: There was no significant difference in two groups with respect to the range of movements or grip strength. One case had delayed union (LC-DCP group) and another had synostosis (LCP group). Plate removal was done in four cases within the study period with no refracture till the presentation of this report. CONCLUSION: LC plating is an effective treatment option for fractures of both bones of forearm. The present study could not prove its superiority over LC-DCP.

Resection and arthrodesis of the knee joint for giant cell tumours of bone.

PURPOSE: To evaluate functional outcomes and complications following resection and arthrodesis of the knee for giant cell tumours (GCTs) of bone, in comparison to treatment by endoprosthetic replacements reported elsewhere. METHODS: 18 men and 14 women aged 18 to 40 (mean, 28) years underwent resection and arthrodesis of the knee for GCTs of bone involving the distal femur (n=17) and proximal tibia (n=15). After wide resection, 2 struts were fashioned from the harvested fibula/ fibulae and inserted into the medullary canal at the resected ends of the tibia and femur. The corresponding ends of the struts were inserted into peg holes made in the unaffected condyles in a divergent fashion. The knee was arthrodesed in 5 to 10 degrees of flexion, with the limb kept 1 cm short. A 95-degree AO condylar bladeplate (10-12 holes) was fixed at the resected ends, with a minimum of 8 cortices purchase. Cancellous bone grafts were placed transversely along the struts and circumferentially over the host-graft junctions. Outcomes and complications were evaluated and compared with those of endoprosthetic arthroplasty reported elsewhere. RESULTS: Patients were followed up for a mean of 8 (range, 3-12) years. The mean size of the tumours was 10x8x6 cm. All patients achieved arthrodesis and full weight bearing without pain within 6 to 10 (mean, 6) months. No shortening, loss of alignment, loosening, implant breakage ensued. One patient had a deep infection and absorption at the host-graft junction. Another had a stress fracture of the fibular strut after plate removal. Two patients had a transient peroneal nerve palsy. One patient had local recurrence and extensive fungation and underwent amputation. The mean functional score was 26 (87% of the full score), compared to 66 to 85% in endoprosthetic arthroplasty reported elsewhere. CONCLUSION: Arthrodesis is a viable alternative to customised arthroplasty and provides a long-lasting and cost-effective reconstruction for average patients in developing countries.

Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design.

Aberrant regulation of Notch signaling has been implicated in tumorigenesis. Proteolytic release of the Notch intracellular domain (NICD) by gamma-secretase plays a key role in Notch-dependent nuclear signaling. gamma-Secretase is an attractive pharmaceutical target for therapeutic intervention in cancer. We describe the potent antitumor effects of PF-03084014, a small molecule that is a reversible, noncompetitive, and selective gamma-secretase inhibitor. The ability of PF-03084014 to inhibit gamma-secretase activity was shown by the reduction of endogenous NICD levels and by the downregulation of Notch target genes Hes-1 and cMyc in the T-cell acute lymphoblastic leukemia (T-ALL) cell line HPB-ALL. PF-03084014 caused cell growth inhibition of several T-ALL cell lines via cell cycle arrest and induction of apoptosis. PF-03084014 treatment also resulted in robust NICD reduction in HBP-ALL xenograft models. Broad antitumor efficacy at well-tolerated dose levels was observed in six Notch-dependent models. Additional mechanism-of-action studies showed inhibition of tumor cell proliferation and induction of apoptosis in HPB-ALL tumors, suggesting that the antitumor activity of PF-03084014 may be mediated by its direct effects on tumor cell growth or survival. Further studies on PF-03084014-induced gastrointestinal toxicity identified an intermittent dosing schedule that displayed reduced body weight loss and sustained antitumor efficacy. We also showed that glucocorticoids abrogated PF-03084014-induced gastrointestinal toxicity and delayed administration of glucocorticoids did not compromise its protection effect. Collectively, the results show that inhibition of Notch signaling by PF-03084014 while minimizing gastrointestinal toxicity presents a promising approach for development of therapies for Notch receptor-dependent cancers. This compound is being investigated for the treatment of T-ALL and advanced solid tumors in phase I clinical trials.

PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy.

The Aurora family of highly related serine/threonine kinases plays a key role in the regulation of mitosis. Aurora1 and Aurora2 play important but distinct roles in the G(2) and M phases of the cell cycle and are essential for proper chromosome segregation and cell division. Overexpression and amplification of Aurora2 have been reported in different tumor types, including breast, colon, pancreatic, ovarian, and gastric cancer. PF-03814735 is a novel, potent, orally bioavailable, reversible inhibitor of both Aurora1 and Aurora2 kinases that is currently in phase I clinical trials for the treatment of advanced solid tumors. In intact cells, the inhibitory activity of PF-03814735 on the Aurora1 and Aurora2 kinases reduces levels of phospho-Aurora1, phosphohistone H3, and phospho-Aurora2. PF-03814735 produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells. Although PF-03814735 produces significant inhibition of several other protein kinases, the predominant biochemical effects in cellular assays are consistent with inhibition of Aurora kinases. Once-daily oral administration of PF-03814735 to mice bearing human xenograft tumors produces a reduction in phosphohistone H3 in tumors at doses that are tolerable and that result in significant inhibition of tumor growth. The combination of PF-03814735 and docetaxel in xenograft mouse tumor models shows additive tumor growth inhibition. These results support the clinical evaluation of PF-03814735 in cancer patients. Mol Cancer Ther; 9(4); 883-94. (c)2010 AACR.

Therapeutic potential of matrix metalloprotease inhibitors in neuropathic pain.

IMPORTANCE OF THE FIELD: Millions of people suffer from neuropathic pain (NP), but the treatment is empirical and results in transient relief in only a few patients. This is primarily because of the poor understanding of the molecular mechanism underlying NP. Following nerve injury, there is a differential and temporal pattern of MMPs expression that coincides with changes in levels of pro-inflammatory cytokines, suggesting that MMPs not only act as mediators for neuroinflammation but might also be directly involved in pain associated with nerve damage. AREAS COVERED IN THIS REVIEW: The present review describes the different mechanisms of NP. The main focus of the review is to highlight the importance of MMPs in NP and their inhibition as a novel approach for treating NP. WHAT THE READER WILL GAIN: A comprehensive overview of the role of MMPs in the pathogenesis of NP and the potential of MMP inhibition as a therapeutic intervention for NP. TAKE HOME MESSAGE: Targeted therapy using specific MMP inhibitors, siRNAs, peptide inhibitors and monoclonal antibodies can provide a better way of treatment by blocking a single MMP and can reduce the side effects of broad-spectrum MMP inhibitors.

Prostaglandin E(2) synthase inhibition as a therapeutic target.

BACKGROUND: Most NSAIDs function by inhibiting biosynthesis of PGE(2) by inhibition of COX-1 and/or COX-2. Since COX-1 has a protective function in the gastro-intestinal tract (GIT), non-selective inhibition of both cycloxy genases leads to moderate to severe gastro-intestinal intolerance. Attempts to identify selective inhibitors of COX-2, led to the identification of celecoxib and rofecoxib. However, long-term use of these drugs has serious adverse effects of sudden myocardial infarction and thrombosis. Drug-mediated imbalance in the levels of prostaglandin I(2) (PGI(2)) and thromboxane A(2) (TXA(2)) with a bias towards TXA(2) may be the primary reason for these events. This resulted in the drugs being withdrawn from the market, leaving a need for an effective and safe anti-inflammatory drug. METHODS: Recently, the focus of research has shifted to enzymes downstream of COX in the prosta glandin biosynthetic pathway such as prostaglandin E(2) synthases. Microsomal prostaglandin E(2) synthase-1 (mPGES-1) specifically isomerizes PGH(2) to PGE(2), under inflammatory conditions. In this review, we examine the biology of mPGES-1 and its role in disease. Progress in designing molecules that can selectively inhibit mPGES-1 is reviewed. CONCLUSION: mPGES-1 has the potential to be a target for anti-inflammatory therapy, devoid of adverse GIT and cardiac effects and warrants further investigation.

Crucial role of cytosolic tryparedoxin peroxidase in Leishmania donovani survival, drug response and virulence.

Leishmania donovani, the causative agent of visceral leishmaniasis, uses a cascade of enzymes that include cytosolic tryparedoxin peroxidase (cTXNPx) for detoxification of peroxides, an event pivotal for survival of digenic parasites living in two disparate biological environments. In this study, we observed an increase in promastigote cTXNPx levels after exposure to H(2)O(2) and this group did not show any cell death; however, exposure to a combination of H(2)O(2) and nitric oxide resulted in significant reduction of cTXNPx levels accompanied by high cell death. The protective relationship between higher levels of cTXNPx and survival was further substantiated by the improved ability of L. donovani promastigotes overexpressing cTXNPx to withstand exposure to H(2)O(2) and nitric oxide combination as compared with vector transfectants. In addition, cTXNPx transfectants demonstrated increased virulence, causing higher parasite burden in macrophages as compared with vector transfectants. Interestingly, the cTXNPx transfectants as promastigotes or amastigotes were resistant to clearance by the anti-leishmanial drug antimony, suggesting a cTXNPx link to drug response. Mechanistically, cTXNPx overexpression was protective against changes in Ca(2+) homeostasis but not against mitochondrial hyperpolarization brought about by exposure to H(2)O(2) and nitric oxide. Therefore, this study provides a link between cTXNPx expression to survival, virulence and drug response in L. donovani.

Calcium phosphate ceramics as bone graft substitutes in filling bone tumor defects.

BACKGROUND: Synthetic bio-inert materials are currently used as an alternative to autogenous bone graft. Calcium hydroxyapatite (HA) and Beta tri-calcium phosphate (beta-TCP), which belong to the calcium phosphate ceramics group, are biocompatible and osteo-conductive. The purpose of this study is to analyse the use of HA and beta-TCP in their ceramic forms as a bone graft substitute in filling bone voids after curettage of benign bone tumors. MATERIALS AND METHODS: Twenty-four patients in the age range of 3.5-55 years (mean 14.3 years) having benign bone tumors with bone defects were filled with bone graft substitute following curettage. In 20 patients bone defects were filled with block/granules of HA ceramic and in four with beta-TCP. Fibular strut graft was packed with HA in four patients. The patients were followed up for an average of 18 months (range 12-36 months). RESULTS: The functional status of the patients at follow-up was evaluated and compared with preoperative functional status. Early incorporation of graft substitutes became evident radiologically between 6 and 10 weeks (Stage I). Complete incorporation (Stage III) was observed in an average of nine months (6-18 months). Clinical healing was observed before radiological healing. The average time taken to return to preoperative function was 14 weeks. There was no recurrence of lesion or growth retardation. CONCLUSION: Calcium hydroxyapatite and beta-TCP are excellent bone graft substitutes for autogenous bone graft in filling voids after curettage of benign bone tumors.

Discovery and pharmacologic characterization of CP-724,714, a selective ErbB2 tyrosine kinase inhibitor.

Amplification and overexpression of erbB2 (Her-2/neu) proto-oncogene has been linked to human malignancies including tumors of the breast, ovary, and stomach. It has been implicated in tumor growth, sensitivity to standard chemotherapy, prognosis of patients, and disease-free survival. Although the clinical use of trastuzumab (Herceptin) has prolonged the survival of breast cancer patients with erbB2-overexpressing tumors, there is an urgent need for more potent and orally bioavailable small-molecule inhibitors. CP-724,714 is a potent inhibitor of erbB2 receptor autophosphorylation in intact cells and is currently undergoing phase I clinical trials. Here, we describe the effects of CP-724,714 in vitro and in vivo in human breast cancer models. CP-724,714 is selective for inhibiting growth of HER2-driven cell lines. In addition, we show that it induces G1 cell cycle block in erbB2-overexpressing BT-474 human breast carcinoma cells and inhibits erbB2 autophosphorylation in xenografts when administered p.o. to athymic mice. It induces a marked reduction of extracellular signal-regulated kinase and Akt phosphorylation, tumor cell apoptosis, and release of caspase-3. P.o. administration (q.d. or b.i.d.) of CP-724,714 inhibits the growth of erbB2-overexpressing tumors in athymic mice without overt adverse effects.

Determination of gibberellins in fermentation broth produced by Fusarium verticilliodes MTCC 156 by high-performance liquid chromatography tandem mass spectrometry.

A method for the detection of gibberellins produced by Fusarium verticilliodes is described using HPLCMS/MS (HPLC tandem MS). A Hypersil (5 microm) octadecylsilane column with methanol/water as eluent in the ratio 3:1 at a flow rate of 0.5 ml/min was used. In the HPLCMS, GA(3) (gibberellic acid; m / z 346.3) eluted at retention time tr=3.08 min, with the corresponding mass chromatogram having peaks at m / z 346.7 and 328.8 corresponding to the M+ and M+-H2O ions respectively. The ethyl acetate extract from the broth, subjected to HPLCMS analysis under similar conditions, showed a constituent with tr=2.13 min, the mass chromatogram of which exhibited peaks at m / z 348.9 and 331.9 corresponding to the MH+ and MH+-H2O ions respectively. Comparison of the MS and MS/MS results (direct infusion) of an authentic sample of GA3 and the ethyl acetate extract from the broth revealed the formation of reduced GA3 in the broth. The present study, utilizing HPLCMS/MS, describes an improved methodology for the unambiguous determination and estimation of gibberellins from fermentation broth.

Pharmacological characterization of CP-547,632, a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy.

Signaling through vascular endothelial growth factor (VEGF) receptors (VEGFRs) is a key pathway initiating endothelial cell proliferation and migration resulting in angiogenesis, a requirement for human tumor growth and metastasis. Abrogation of signaling through VEGFR by a variety of approaches has been demonstrated to inhibit angiogenesis and tumor growth. Small molecule inhibitors of VEGFR tyrosine kinase have been shown to inhibit angiogenesis, inhibit tumor growth, and prevent metastases. Our goal was to discover and characterize an p.o. active VEGFR-2 small molecule inhibitor. A novel isothiazole, CP-547,632, was identified as a potent inhibitor of the VEGFR-2 and basic fibroblast growth factor (FGF) kinases (IC(50) = 11 and 9 nM, respectively). It is selective relative to epidermal growth factor receptor, platelet-derived growth factor beta, and other related TKs. It also inhibits VEGF-stimulated autophosphorylation of VEGFR-2 in a whole cell assay with an IC(50) value of 6 nM. After oral administration of CP-547,632 to mice bearing NIH3T3/H-ras tumors, VEGFR-2 phosphorylation in tumors was inhibited in a dose-dependent fashion (EC(50) = 590 ng/ml). These plasma concentrations correlated well with the observed concentrations of the compound necessary to inhibit VEGF-induced corneal angiogenesis in BALB/c mice. A sponge angiogenesis assay was used to directly compare the inhibitory activities of CP-547,632 against FGF receptor 2 or VEGFR-2; this compound potently inhibits both basic FGF and VEGF-induced angiogenesis in vivo. The antitumor efficacy of this agent was evaluated after once daily p.o. administration to athymic mice bearing human xenografts and resulted in as much as 85% tumor growth inhibition. CP-547,632 is a well-tolerated, orally-bioavailable inhibitor presently under clinical investigation for the treatment of human malignancies.

The biological and biochemical effects of CP-654577, a selective erbB2 kinase inhibitor, on human breast cancer cells.

Aberrant expression or activity of epidermal growth factor receptor (EGFr) or the closely related p185(erbB2) can promote cell proliferation and survival and thereby contribute to tumorigenesis. Specific antibodies and low molecular-weight tyrosine kinase inhibitors of both proteins are in clinical trials for cancer treatment. CP-654577 is a potent inhibitor selective for p185(erbB2), relative to EGFr tyrosine kinase, and selectively reduces erbB2 autophosphorylation in intact cells. Treatment of SKBr3 human breast cancer cells with CP-654577 reduces the levels of the activated form of mitogen-activated protein kinase, increases the levels of cyclin-dependent kinase inhibitor p27(kip1) and reduces expression of cyclins D and E. These biochemical changes result in a reduced level of phosphorylated retinoblastoma protein and an inhibition of cell-cycle progression at G(1). Apoptosis is triggered in both SKBr3 and another high erbB2-expressing cell line, BT474, by exposure to 1 micro M CP-654577, but this effect is not observed in MCF7 cells that express low erbB2. Levels of activated Akt, an important positive regulator of cell survival, are reduced within 2 h of exposure to 250 nM CP-654577, and this may contribute to the increased apoptosis. These biochemical effects are distinct from those produced by Tarceva, a selective EGFr inhibitor. The antitumor activity of CP-654577 was investigated in athymic mice bearing s.c. tumors from Fischer rat embryo fibroblasts transfected with erbB2. CP-654577 produced a dose-dependent reduction of p185(erbB2) autophosphorylation and inhibited the growth of these tumors. CP-654577 warrants further evaluation in tumors with high expression of p185(erbB2) and may differ from selective EGFr inhibitors or nonselective dual EGFr/erbB2 inhibitors in efficacy and therapeutic index.